Safford grew up from the age of three in Crete, Illinois. During the 1850s she taught school while living with an older brother successively in Joliet, Shawneetown, and Cairo, Illinois. At the outbreak of the Civil War in the spring of 1861, Cairo became a town of some strategic importance because of its situation at the confluence of the Ohio and Mississippi rivers. The town was quickly occupied by volunteer troops from Chicago, and almost as quickly a variety of epidemic diseases broke out in the hastily constructed camps behind the levee. Safford began visiting the camps to tend the sick and to distribute food she had prepared. She gradually won the respect of officers and surgeons who had initially opposed her, and she was soon permitted to draw upon supplies collected and forwarded by the U.S. Sanitary Commission. By summer she was working closely with “Mother” Mary Ann Bickerdyke, who gave her some training in nursing. In November 1861 Safford nursed the wounded on the battlefield at Belmont, Missouri. In February 1862 she and Bickerdyke helped transport wounded from Fort Donelson to Cairo, and in April that year, following the Battle of Shiloh (Pittsburg Landing) in southwestern Tennessee, she worked aboard the hospital ship Hazel Dell. By that time her almost ceaseless labours had left her utterly exhausted, and she saw no more service during the war.

After an extended convalescent tour of Europe, Safford returned to the United States determined to become a physician. She graduated from the New York Medical College for Women in 1869 and then pursued advanced training in Europe for three years. At the University of Breslau, Germany (now Wrocław, Poland), she became the first woman to perform an ovariotomy. In 1872 she opened a private practice in Chicago. The next year, after her marriage to a Bostonian, she moved her practice to that city and became professor of women’s diseases at the Boston University School of Medicine and a staff physician at the Massachusetts Homeopathic Hospital. She retired from medical practice in 1886.